Manganese injection into the rat striatum produces excitotoxic lesions by impairing energy metabolism.

There is compelling evidence that excessive exposure to manganese (Mn) produces neurotoxicity, especially in the basal ganglia, resulting in a dystonic Parkinsonian disorder. Several experimental or clinical observations suggest that Mn neurotoxicity could involve impairment of energy metabolism. We examined the neurotoxic effects of Mn following local intrastriatal injection. Three hours after the injection of 2 mumol of MnCl2 into rat striatum, ATP levels were reduced to 51% of the control side and lactate level were increased by 97%, indicating an impairment of oxidative metabolism. Neurochemical analysis of the striata 1 week after Mn injection showed changes consistent with a N-methyl-D-aspartate (NMDA) excitotoxic lesion. Dopamine, gamma-aminobutyric acid, and substance P concentrations showed dose-dependent significant decreases, but concentrations of somatostatin-like immunoreactivity and neuropeptide Y-like immunoreactivity were unchanged. The lesions were blocked by prior removal of the cortico-striatal glutamatergic input or by treatment with the noncompetitive NMDA antagonist MK-801. These findings indicate that Mn neurotoxicity involves a NMDA receptor-mediated process similar to that we have previously found with two characterized mitochondrial toxins, aminooxyacetic acid, and 1-methyl-4-phenylpyridinium. Our results show that Mn may produce neuronal degeneration by an indirect excitotoxic process secondary to its ability to impair oxidative energy metabolism.

Somatostatin and neuropeptide Y concentrations in pathologically graded cases of Huntington's disease.

Somatostatin and neuropeptide Y concentrations have previously been reported to be increased in the basal ganglia in Huntington's disease (HD). In the present study we have extended these findings by examining both somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) in cases of HD, which were graded according to the severity of pathological degeneration in the striatum. In addition, we surveyed a large number of subcortical nuclei and cortical regions for alterations. Both SLI and NPYLI were significantly increased about threefold in the caudate, putamen, and the nucleus accumbens. Increases in mild and severe grades were similar, which is consistent with a relative but not absolute sparing of striatal aspiny neurons in which somatostatin and neuropeptide Y are colocalized. Significant increases of NPYLI were also found in the external pallidum, subthalamic nucleus, substantia nigra compacta, claustrum, anterior and dorsomedial thalamus, bed nucleus of the stria terminalis, and locus ceruleus. SLI was significantly increased in the external pallidum, red nucleus, and locus ceruleus. Measurements of both neuropeptides were made in 24 regions of the cerebral cortex. Significant increases in both NPYLI and SLI were found in the frontal cortex (Brodmann areas 6, 8, 9, 10, 11, and 45) and temporal cortex (Brodmann area 21), whereas NPYLI was also increased in Brodmann areas 12, 20-22, 25, and 42. Alterations in the cerebral cortex were as pronounced in cases with mild striatal pathological changes as in those with severe striatal pathological changes. These alterations may occur early in HD and could reflect a selective sparing of somatostatin-neuropeptide Y cortical neurons combined with cortical atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)